A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry

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Abstract
Cell cycle re-entry requires the growth factor-stimulation of at least two distinct classes of protein kinases: (i) the p42/p44 MAP kinases activated by the Ras>Raf>MKK cascade and (ii) the G1 cyclin-dependent protein kinases (CDKs). Specific inactivation of either class of kinase arrests fibroblasts in G1. Growth factors promote nuclear translocation and persistent activation of p42/p44 MAP kinases during the entire G0/G1 period. Here, we demonstrate that induction of cyclin D1, and therefore cdk4/6 activity associated with, is positively controlled by the p42/p44 MAP kinase cascade whereas the parallel cytokines/stress-activated p38MAP kinase cascade is antagonistic. Finally, using an antisense approach we demonstrate that p27Kip1 plays a key role in setting the growth factor-dependency of the GO state.